Therapeutic amides and related compounds

ABSTRACT

Disclosed herein are compounds useful in treating glaucoma, inflammatory bowel disease, the stimulation of hair growth, and the stimulation of the conversion of vellus hair to terminal hair. The compounds themselves are herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is based, and claims priority under 35 U.S.C. §120 toU.S. Provisional Patent Application No. 61/023,365 filed on Jan. 24,2008, and which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

The prostaglandin E analog shown below is disclosed in the followingdocuments, expressly incorporated herein by reference: U.S. Pat. No.5,462,968; U.S. Pat. No. 5,698,598; and U.S. Pat. No. 6,090,847.

Other EP₂ selective agonists are disclosed in U.S. patent applicationSer. No. 11/009,298, filed Dec. 10, 2004 (now U.S. Pat. No. 7,091,231issued Aug. 15, 2006). Prostaglandin EP₂ selective agonists are believedto have several medical uses. For example, U.S. Pat. No. 6,437,146teaches the use of prostaglandin EP₂ selective agonists “for treating orpreventing inflammation and pain in joint and muscle (e.g., rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis,juvenile arthritis, etc.), inflammatory skin condition (e.g., sunburn,burns, eczema, dermatitis, etc.), inflammatory eye condition (e.g.,conjunctivitis, etc.), lung disorder in which inflammation is involved(e.g., asthma, bronchitis, pigeon fancier's disease, farmer's lung,etc.), condition of the gastrointestinal tract associated withinflammation (e.g., aphthous ulcer, Chrohn's disease, atrophicgastritis, gastritis varialoforme, ulcerative colitis, coeliac disease,regional ileitis, irritable bowel syndrome, etc.), gingivitis,inflammation, pain and tumescence after operation or injury, pyrexia,pain and other conditions associated with inflammation, allergicdisease, systemic lupus crythematosus, scleroderma, polymyositis,tendinitis, bursitis, periarteritis nodose, rheumatic fever, Sjgren'ssyndrome, Behcet disease, thyroiditis, type I diabetes, diabeticcomplication (diabetic microangiopathy, diabetic retinopathy, diabeticneohropathy, etc.), nephrotic syndrome, aplastic anemia, myastheniagravis, uveitis contact dermatitis, psoriasis, Kawasaki disease,sarcoidosis, Hodgkin's disease, Alzheimers disease, kidney dysfunction(nephritis, nephritic syndrome, etc.), liver dysfunction (hepatitis,cirrhosis, etc.), gastrointestinal dysfunction (diarrhea, inflammatorybowel disease, etc.) shock, bone disease characterized by abnormal bonemetabolism such as osteoporosis (especially, postmenopausalosteoporosis), hypercalcemia, hyperparathyroidism, Paget's bonediseases, osteolysis, hypercalcemia of malignancy with or without bonemetastases, rheumatoid arthritis, periodonritis, osteoarthritis,ostealgia, osteopenia, cancer cachexia, calculosis, lithiasis(especially, urolithiasis), solid carcinoma, mesangial proliferativeglomerulonephritis, edema (e.g. cardiac edema, cerebral edema, etc.),hypertension such as malignant hypertension or the like, premenstrualtension, urinary calculus, oliguria such as the one caused by acute orchronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No. 6,710,072 teaches the use of EP2 agonists for thetreatment or prevention of “osteoporosis, constipation, renal disorders,sexual dysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

SUMMARY OF THE INVENTION

Disclosed herein are compounds useful in treating glaucoma, inflammatorybowel disease, the stimulation of hair growth, and the stimulation ofthe conversion of vellus hair to terminal hair. The compounds themselvesare disclosed below.

DESCRIPTION OF THE INVENTION

Disclosed herein is a compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interphenylene or monocyclic heterointerarylene, the sumof m and o is 1, 2, 3, or 4, and wherein one CH₂ may be replaced by S orO;E is SO₂, CO, or CS;G is alkyl, aryl or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10carbon atoms; andB is substituted aryl or substituted heteroaryl.

In relation to the identity of A disclosed in the chemical structurespresented herein, A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interphenylene ormonocyclic heterointerarylene, the sum of m and o is 1, 2, 3, or 4, andwherein one CH₂ may be replaced with S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S and/or O. For example,while not intending to limit the scope of the invention in any way, Amay be a moiety where S replaces one or two carbon atoms such as one ofthe following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be a moiety where O replaces one or two carbon atomssuch as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have an O replacing one carbon atom and an S replacinganother carbon atom, such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interphenylene or monocyclic heterointerarylene, the sum of m ando is 1, 2, 3, or 4, and wherein one CH₂ may be replaced with S or O. Inother words, while not intending to limit the scope of the invention inany way,

in one embodiment A comprises 1, 2, 3, or 4 CH₂ moieties and Ar, e.g.—CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂Ar—(CH₂)₂—, —(CH₂)₂—Ar—(CH₂)₂—,and the like;

in another embodiment A comprises: O; 0, 1, 2, or 3 CH₂ moieties; andAr, e.g., —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—,—O—CH₂—Ar—(CH₂)₂, and the like; or

in another embodiment A comprises: S; 0, 1, 2, or 3 CH₂ moieties; andAr, e.g., —S—Ar—, Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—,—S—CH₂—Ar—(CH₂)₂, —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O.

Interphenylene is phenyl which connects two other parts of a molecule,i.e. the two parts are bonded to the ring in two distinct ringpositions. Monocyclic heterointerarylene refers to a heterocyclic ringhaving 5 or 6 atoms, which is aromatic and connects two other parts ofthe molecule. Unsubstituted interphenylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted intephenylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, wherein the heavy atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. Any number of hydrogen atoms required for aparticular substituent will also be included. A substituent must bestable enough for the compound to be useful as described herein. Inaddition to the atoms listed above, a substituent may also have a metalcation or any other stable cation having an atom not listed above if thesubstituent is acidic and the salt form is stable. For example, —OH mayform an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺ salt. Any cation of thesalt is not counted in the “4 or less heavy atoms.” Thus, thesubstituent may be

hydrocarbyl having up to 4 carbon atoms, including alkyl up to C₄,alkenyl, alkynyl, and the like;

hydrocarbyloxy up to C₃;

organic acid such as CO₂H, SO₃H, P(O)(OH)₂, and the like, and saltsthereof; CF₃;

halo, such as F, Cl, or Br;

-   -   hydroxyl;    -   NH₂ and alkylamine functional groups up to C₃;        other N or S containing substituents such as CN, NO₂, and the        like;        and the like.

In one embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterphenylene, the sum of m and o is 1, 2, or 3, and wherein one CH₂may be replaced with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂—Ar—OCH₂— and Ar is interphenylene. In another embodiment, Ar isattached at the 1 and 3 positions, otherwise known as m-interphenylene,such as when A has the structure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph- wherein one CH₂ may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)Ar.

In another embodiment A is —CH₂O(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)₃—.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mph-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-methoxymethylphenyl.

In another embodiment A is 3-(3-propyl)phenyl.

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

Compounds according to the each of the structures depicted below, andpharmaceutically acceptable salts thereof, and prodrugs thereof, arecontemplated as individual embodiments. In other words, each structurerepresents a different embodiment.

E is SO₂, CO, or CS. Thus, each of the structures below is contemplated.These structures, or pharmaceutically acceptable salts thereof, orprodrugs thereof, individually represent a compound which is anembodiment contemplated herein. In other words, each structurerepresents a different embodiment.

G is alkyl, aryl or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10carbon atoms. Thus, each of the structures below is contemplated. Thesestructures, or pharmaceutically acceptable salts thereof, or prodrugsthereof, individually represent a compound which is an embodimentcontemplated herein. In other words, each structure represents adifferent embodiment.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.one or more ring carbons are substituted by N, O, and/or S. While notintending to be limiting, examples of heteroaryl include thienyl,pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, andthe like.

A substituent of aryl or heteroaryl may have up to 20 non-hydrogen atomseach in any stable combination and as many hydrogen atoms as necessary,wherein the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. However, the total number of non-hydrogen atomson all of the substituents combined must also be 20 or less. Asubstituent must be sufficiently stable for the compound to be useful asdescribed herein. In addition to the atoms listed above, a substituentmay also have a metal cation or other stable cation having an atom notlisted above if the substituent is acidic and the salt form is stable.For example, —OH may form an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺salt. Thus, while not intending to limit the scope of the invention inany way, a substituent may be:

hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen suchas alkyl, alkenyl, alkynyl, and the like, including linear, branched orcyclic hydrocarbyl, and combinations thereof;

hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,O-cyclohexyl, etc, up to 19 carbon atoms;

other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the like;

thioether substituents including S-hydrocarbyl and other thioethersubstituents;

hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,etc, up to 19 carbon atoms;

nitrogen substituents such as NO₂, CN, and the like, including

amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like up to 19 carbonatoms;

carbonyl substituents, such as CO₂H, ester, amide, and the like;

halogen, such as chloro, fluoro, bromo, and the like fluorocarbyl, suchas CF₃, CF₂CF₃, etc.;

phosphorous substituents, such as PO₃ ²⁻, and the like;

sulfur substituents, including S-hydrocarbyl, SH, SO₃H, SO₂-hydrocarbyl,SO₃-hydrocarbyl, and the like.

Substituted aryl or heteroaryl may have as many substituents as the ringor ring system will bear, and the substituents may be the same ordifferent. Thus, for example, an aryl ring or a heteroaryl ring may besubstituted with chloro and methyl; methyl, OH, and F; CN, NO₂, andethyl; and the like including any conceivable substituent or combinationof substituent possible in light of this disclosure.

Substituted aryl or substituted heteroaryl also includes a bicyclic orpolycyclic ring system wherein one or more rings are aromatic and one ormore rings are not. For example, indanonyl, indanyl, indanolyl,tetralonyl, and the like are substituted aryl. For this type ofpolycyclic ring system, an aromatic or heteroaromatic ring, not anon-aromatic ring, must be attached to the remainder of the molecule. Inother words, in any structure depicting —B herein, where — is a bond,the bond is a direct bond to an aromatic ring.

In one embodiment, B is substituted aryl or heteroaryl.

In another embodiment B is substituted phenyl.

In another embodiment B has no halogen atoms.

In another embodiment B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxybutyl)phenyl.

In another embodiment B is 4-(1-hydroxyheptyl)phenyl.

In another embodiment B is 4-(1-hydroxyhexyl)phenyl.

In another embodiment B is 4-(1-hydroxypentyl)phenyl.

In another embodiment B is 4-(1-hydroxypropyl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

In another embodiment B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 3-(hydroxy)(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

In another embodiment B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-tert-butylphenyl.

In another embodiment B is 4-hexylphenyl.

In another embodiment B is 4-(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxycyclobutyl)phenyl.

In another embodiment B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

In another embodiment B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

In another embodiment B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

In another embodiment B is 4-(cyclohexylmethyl)phenyl.

In another embodiment B is 4-(hydroxy(phenyl)methyl)phenyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C1-10 hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁-10 hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C1-10 hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C1-10 hydrocarbyl.

“C1-10” hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 carbon atoms.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

Alkyl is hydrocarbyl having no double or triple bonds including:

linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl,and the like;

branched alkyl such as isopropyl, branched butyl isomers (i.e.sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e. isopentyl,etc), branched hexyl isomers, and higher branched alkyl fragments;

cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc.; and alkyl fragments consisting of both cyclic andnoncyclic components, whether linear or branched, which may be attachedto the remainder of the molecule at any available position includingterminal, internal, or ring carbon atoms.Alkenyl is hydrocarbyl having one or more double bonds including linearalkenyl, branched alkenyl, cyclic alkenyl, and combinations thereof inanalogy to alkyl.Alkynyl is hydrocarbyl having one or more triple bonds including linearalkynyl, branched alkynyl, cyclic alkynyl and combinations thereof inanalogy to alkyl.Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like. Aryl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.Arylalkyl is alkyl which is substituted with aryl. In other words alkylconnects aryl to the remaining part of the molecule. Examples are—CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.Unconjugated dienes or polyenes have one or more double bonds which arenot conjugated. They may be linear, branched, or cyclic, or acombination thereof. Combinations of the above are also possible.

Hydroxyalkylaryl is aryl, including phenyl, heteroaryl and the like,which is substituted with hydroxyalkyl. Hydroxyalkyl is alkyl, whetherlinear, branched, cyclic, or a combination thereof, which has a hydroxylsubstituent. For example, CHOH(CH₂)₄CH₃ is hydroxyalkyl, andphenyl-CHOH(CH₂)₄CH₃, is hydroxyalkylaryl.

Thus, each of the structures below is contemplated. These structures, orpharmaceutically acceptable salts thereof, or prodrugs thereof,individually represent a compound which is an embodiment contemplatedherein. In other words, each structure represents a differentembodiment.

In the above embodiments, x is 5, 6, or 7, and y+z is 2x+1.

In one embodiment, x is 5 and y+z is 11.

In another embodiment, x is 6 and y+z is 13.

In another embodiment, x is 7 and y+z is 15.

Hypothetical examples of useful compounds are shown below.

COMPOUND EXAMPLES

The following are hypothetical examples of useful compounds:

Compound Example 1

A compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interphenylene or monocyclic heterointerarylene, the sumof m and o is 1, 2, 3, or 4, and wherein one CH₂ may be replaced by S orO;E is SO₂, CO, or CS;G is alkyl, aryl or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10carbon atoms; andB is substituted aryl or substituted heteroaryl.

Compound Example 2

The compound according to compound example 1 wherein B is substitutedphenyl.

Compound Example 3

The compound according to compound example 1 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 4

The compound according to compound example 3 wherein R is alkyl.

Compound Example 5

The compound according to compound example 3 wherein R is arylalkyl.

Compound Example 6

The compound according to compound example any one of compound examples1 to 5 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 7

The compound according to compound example 1 wherein A is(3-methylphenoxy)methyl.

Compound Example 8

The compound according to compound example 1 wherein A is(4-but-2-ynyloxy)methyl.

Compound Example 9

The compound according to compound example 1 wherein A is2-(2-ethylthio)thiazol-4-yl.

Compound Example 10

The compound according to compound example 1 wherein A is2-(3-propyl)thiazol-5-yl.

Compound Example 11

The compound according to compound example 1 wherein A is3-methoxymethyl)phenyl.

Compound Example 12

The compound according to compound example 1 wherein A is3-(3-propylphenyl.

Compound Example 13

The compound according to compound example 1 wherein A is3-methylphenethyl.

Compound Example 14

The compound according to compound example 1 wherein A is4-(2-ethyl)phenyl.

Compound Example 15

The compound according to compound example 1 wherein A is 4-phenethyl.

Compound Example 16

The compound according to compound example 1 wherein A is4-methoxybutyl.

Compound Example 17

The compound according to compound example 1 wherein A is5-(methoxymethyl)furan-2-yl.

Compound Example 18

The compound according to compound example 1 wherein A is5-(methoxymethyl)thiophen-2-yl.

Compound Example 19

The compound according to compound example 1 wherein A is5-(3-propyl)furan-2-yl.

Compound Example 20

The compound according to compound example 1 wherein A is5-(3-propyl)thiophen-2-yl.

Compound Example 21

The compound according to compound example 1 wherein A is 6-hexyl.

Compound Example 22

The compound according to compound example 1 wherein A is(Z)-6-hex-4-enyl.

Compound Example 23

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

Compound Example 24

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

Compound Example 25

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxy-2-methylpropyl)phenyl.

Compound Example 26

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxybutyl)phenyl.

Compound Example 27

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxyheptyl)phenyl.

Compound Example 28

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxyhexyl)phenyl.

Compound Example 29

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxypentyl)phenyl.

Compound Example 30

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxypropyl)phenyl.

Compound Example 31

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

Compound Example 32

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

Compound Example 33

The compound according to any one of compound examples 1 and 7-22wherein B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

Compound Example 34

The compound according to any one of compound examples 1 and 7-22wherein B is 2,3-dihydro-1H-inden-5-yl.

Compound Example 35

The compound according to any one of compound examples 1 and 7-22wherein B is 3-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

Compound Example 36

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

Compound Example 37

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

Compound Example 38

The compound according to any one of compound examples 1 and 7-22wherein B is 4-tert-butylphenyl.

Compound Example 39

The compound according to any one of compound examples 1 and 7-22wherein B is 4-hexylphenyl.

Compound Example 40

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxy-2-phenylethyl)phenyl.

Compound Example 41

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

Compound Example 42

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(1-hydroxycyclobutyl)phenyl.

Compound Example 43

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

Compound Example 44

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

Compound Example 45

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

Compound Example 46

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(cyclohexylmethyl)phenyl.

Compound Example 47

The compound according to any one of compound examples 1 and 7-22wherein B is 4-(hydroxy(phenyl)methyl)phenyl.

The following are hypothetical examples of compositions, kits, methods,uses, and medicaments employing the hypothetical compound examples.

Composition Example

A composition comprising a compound according to any one of compoundexamples 1 to 47, wherein said composition is a liquid which isophthalmically acceptable.

Medicament Examples

Use of a compound according to any one of compound examples 1 to 47 inthe manufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

A medicament comprising a compound according to any one of compoundexamples 1 to 47, wherein said composition is a liquid which isophthalmically acceptable.

Method Example

A method comprising administering a compound according to any one ofcompound examples 1 to 47 to a mammal for the treatment of glaucoma orocular hypertension.

Kit Example

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 47, a container, and instructions foradministration of said composition to a mammal for the treatment ofglaucoma or ocular hypertension.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle 0-40 tonicity adjuster 1-10 buffer 0.01-10   pHadjuster q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%Applications for Stimulating Hair Growth

In one embodiment, the compounds disclosed herein can be useful in thetreatment of baldness and/or hair loss. Alopecia (baldness) is adeficiency of either normal or abnormal hair, and is primarily acosmetic problem in humans. It is a deficiency of terminal hair, thebroad diameter, colored hair that is readily seen. However, in the socalled bald person, although there is a noticeable absence of terminalhair, the skin does contain vellus hair, which is a fine colorless hairwhich may require microscopic examination to determine its presence.This vellus hair is a precursor to terminal hair.

The compounds described herein can be used to stimulate, such as theconversion of vellus hair to growth as terminal hair, as well asincreasing the rate of growth of terminal hair. The utility of thecompounds described herein for the simulation of hair growth wasdiscovered as follows.

In the course of treating patients having glaucoma, treatment may onlybe appropriate in one eye. Within the course of daily practice, it wasdiscovered that a patient who had been treated with bimatoprost, aprostaglandin analogue, developed lashed that were longer, thicker, andfuller in the treated eye than in the non-treated eye. On examination,the difference was found to be very striking. The lashes were longer andhad a fuller, denser appearance in the treated eye. The lash appearanceon the lids of the treated eyes would have appeared quite attractive ifit represented a bilateral phenomenon. As a result of its asymmetricnature, the long lashes on one side could be construed as disturbingfrom a cosmetic standpoint. A systemic examination was preformed as aresult of the asymmetric phenomenon. It soon became apparent that thisaltered appearance was not an isolated finding. Comparison of the lidsof patients who were taking bimatoprost in only one eye revealed subtlechanges in the lashed and adjacent hairs of the bimatoprost-treated sidein several patients. Definite differences could be identified to varyingdegrees in the lashes and adjacent hairs of all patients who were takingthe drug on a unilateral basis for longer than 6 months.

The changes in the lashes were apparent on gross inspection in severalpatients once attention was focused on the issue. In those with lightcolored hair and lashes, the differences were only seen easily with theaid of the high magnification and lighting capabilities of the slit lampbiomicroscope. In the course of glaucoma follow-up examination,attention is generally immediately focused on the eye itself. As aresult of the high power magnification needed only one eye is seen at atime and the eye is seen at a high enough power that the lashes are notin focus. At these higher powers, any lash asymmetry between the twoeyes is not likely to be noticed except by careful systematic comparisonof the lashes and adjacent hairs of the eyelids of the two eyes.

Observed parameters leading to the conclusion that more robust hairgrowth occurred in the treatment area following administration of theprostaglandin analogue were multiple. They included increased length oflashed, increased number of lashes along the normal lash line, increasedthickness and luster of lashes, increased auxiliary lash-like terminalhair in transitional areas adjacent to areas of normal lash growth,increased auxiliary lash-like terminal hairs at the medial and lateralcanthal area, increased pigmentation of the lashes, increased numbers,increased length, as well as increased luster, and thickness of finehair on the skin of the adjacent lid, and finally, increasedperpendicular angulation of lashes and lash-like terminal hairs. Theconclusion that hair growth is stimulated by prostaglandin analoguessuch as bimatoprost is thus supported not by evidence of a difference ina single parameter, but is based on multiple parameters of hairappearance in treated versus control areas in many subjects.

The compounds described herein are prostaglandin analogues and thereforehave similar activities as bimatoprost, contain structural similarities,and therefore are expected to stimulate hair growth and stimulation ofthe conversion of vellus hair to terminal hair. In one embodiment, thecompounds described herein and their prodrugs can be used for thestimulation of hair growth. As used herein, hair growth includes hairassociated with the scalp, eyebrows, eyelids, beard, and other areas ofthe skin of animals.

In one embodiment, the compound is mixed with a dermatologicallycompatible vehicle or carrier. The vehicle, which may be employed forpreparing compositions as described herein, may comprise, for example,aqueous solutions such as e.g., physiological salines, oil solutions, orointments. The vehicle furthermore may contain dermatologicallycompatible preservatives such as e.g., benzalkonium chloride,surfactants like e.g., polysorbate 80, liposomes or polymers, forexample, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone andhyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

In one embodiment, dermatological compositions can be formulated fortopical treatment for the stimulation of hair growth which comprises aneffective hair growth simulating amount of one or more compounds asdefined above and a dermatologically compatible carrier. Effectiveamounts of the active compounds may be determined by one of ordinaryskill in the art, but will vary depending on the compound employed,frequency of application and desired result. The compound will generallyrange from about 0.0000001 to about 50% by weight of the dermatologicalcomposition. Preferably, the compound will range from about 0.001 toabout 50% by weight of total dermatological composition, more preferablyfrom about 0.1 to about 30% by weight of the composition.

In one embodiment, the application of the present compounds forstimulation of hair growth finds applications in mammalian species,including both humans and animals. In humans, the compounds describedherein can be applied for example, to the scalp, face beard, head, pubicarea, upper lip, eyebrows, and eyelids. In animal raised for theirpelts, e.g., mink, the compounds described herein can be applied overthe entire surface of the body to improve the overall pelt forcommercial reasons. The process can also be used for cosmetic reasons inanimals, e.g., applied to the skin of dogs and cats having bald patchesdue to mange or other diseases causing a degree of alopecia.

The pharmaceutical compositions contemplated for the stimulation of hairgrowth include pharmaceutical compositions suited for topical and localaction. The term “topical” as employed herein relates to the use of acompound, as described herein, incorporated in a suitable pharmaceuticalcarrier, and applied at the site of thinning hair or baldness forexertion of local action. Accordingly, such topical compositions includethose pharmaceutical forms in which the compound is applied externallyby direct contact with the skin to be treated. Conventionalpharmaceutical forms for this purpose include ointments, liniments,creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and thelike, and may be applied in patches or impregnated dressings dependingon the part of the body to be treated. The term “ointment” embracesformulations (including creams) having oleaginous, water-soluble andemulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, aswell as mixtures of these.

Typically, the compounds can be applied repeatedly for the sustainedperiod of time topically on the part of the body to be treated, forexample, the eyelids, eyebrows, to skin or scalp. The preferred dosageregimen will generally involve regular, such as daily, administrationfor a period of treatment of at least one month, more preferably atleast three months, and most preferably, at least six months.

For topical use on the eyelids or eyebrows, the active compounds can beformulated in aqueous solutions, creams, ointments, or oils exhibitingphysiological acceptable osmolarity by addition of pharmaceuticallyacceptable buffers and salts. such formulations may or may not,depending on the dispenser, contain preservatives such as benzalkoniumchloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid andthe like as additives. Furthermore, particularly aqueous solutions maycontain viscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or poly alcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matricies may also be employed as well assoluble and insoluble ocular inserts, for instance, based on substancesforming in situ gels. Depending on the actual formation and compound tobe used, various amounts of the drug and different dose regimens may beemployed. Typically, the daily amount of compound for treatment of theeyelid may be about 0.1 ng to about 100 mg per eyelid.

For topical use on the skin and scalp, the compound can beadvantageously formulated using ointments, creams, liniments or patchesas a carrier of the active ingredient. Also, these formulations may ormay not contain preservatives, depending on the dispenser and nature ofuse. Such preservatives include those mentioned above, and methyl-,propyl-, or butyl-parahydroxybenzoic acid, betain, chlorhexidine,benzalkonium chloride, and the like. Various matricies for the slowrelease delivery may also be used. Typically, the dose to be applied onthe scalp is in the range of about 0.1 ng to about 100 mg per day, morepreferably about 1 ng to about 10 mg per day, and most preferably about10 ng to about 1 mg per day depending on the compound and theformulation. To achieve the daily amount of medication depending on theformulation, the compound may be administered once or several timesdaily with or without antioxidants.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The compounds disclosed herein are also useful in combination with otherdrugs useful for the treatment of glaucoma or other conditions.

For the treatment of glaucoma, combination treatment with the followingclasses of drugs are contemplated:

β-Blockers (or β-adrenergic antagonists) including carteolol,levobunolol, metiparanolol, timolol hemihydrate, timolol maleate,β1-selective antagonists such as betaxolol, and the like, orpharmaceutically acceptable salts or prodrugs thereof;

Adrenergic Agonists including

non-selective adrenergic agonists such as epinephrine borate,epinephrine hydrochloride, and dipivefrin, and the like, orpharmaceutically acceptable salts or prodrugs thereof; and

α₂-selective adrenergic agonists such as apraclonidine, brimonidine, andthe like, or pharmaceutically acceptable salts or prodrugs thereof;

Carbonic Anhydrase Inhibitors including acetazolamide, dichlorphenamide,methazolamide, brinzolamide, dorzolamide, and the like, orpharmaceutically acceptable salts or prodrugs thereof;

Cholinergic Agonists including

direct acting cholinergic agonists such as carbachol, pilocarpinehydrochloride, pilocarbine nitrate, pilocarpine, and the like, orpharmaceutically acceptable salts or prodrugs thereof;

chlolinesterase inhibitors such as demecarium, echothiophate,physostigmine, and the like, or pharmaceutically acceptable salts orprodrugs thereof;

Glutamate Antagonists and other neuroprotective agents such as Ca²⁺channel blockers such as memantine, amantadine, rimantadine,nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines,verapamil, emopamil, benzothiazepines, bepridil,diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and relateddrugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine,2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine,barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride, andthe like, or pharmaceutically acceptable salts or prodrugs thereof;Prostamides such as bimatoprost, or pharmaceutically acceptable salts orprodrugs thereof; andProstaglandins including travoprost, UFO-21, chloprostenol,fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone,latanoprost and the like.Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940 andthe like,or pharmaceutically acceptable salts or prodrugs thereof.

For treatment of diseases affecting the eye including glaucoma, thesecompounds can be administered topically, periocularly, intraocularly, orby any other effective means known in the art.

In addition to the treatment of glaucoma, prostaglandin EP₂ selectiveagonists are believed to have several medical uses. For example, U.S.Pat. No. 6,437,146 teaches the use of prostaglandin EP₂ selectiveagonists “for treating or preventing inflammation and pain in joint andmuscle (e.g., rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis, juvenile arthritis, etc.), inflammatoryskin condition (e.g., sunburn, burns, eczema, dermatitis, etc.),inflammatory eye condition (e.g., conjunctivitis, etc.), lung disorderin which inflammation is involved (e.g., asthma, bronchitis, pigeonfancier's disease, farmer's lung, etc.), condition of thegastrointestinal tract associated with inflammation (e.g., aphthousulcer, Chrohn's disease, atrophic gastritis, gastritis varialoforme,ulcerative colitis, coeliac disease, regional ileitis, irritable bowelsyndrome, etc.), gingivitis, inflammation, pain and tumescence afteroperation or injury, pyrexia, pain and other conditions associated withinflammation, allergic disease, systemic lupus crythematosus,scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodose,rheumatic fever, Sjgren's syndrome, Behcet disease, thyroiditis, type Idiabetes, diabetic complication (diabetic microangiopathy, diabeticretinopathy, diabetic neohropathy, etc.), nephrotic syndrome, aplasticanemia, myasthenia gravis, uveitis contact dermatitis, psoriasis,Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimers disease,kidney dysfunction (nephritis, nephritic syndrome, etc.), liverdysfunction (hepatitis, cirrhosis, etc.), gastrointestinal dysfunction(diarrhea, inflammatory bowel disease, etc.) shock, bone diseasecharacterized by abnormal bone metabolism such as osteoporosis(especially, postmenopausal osteoporosis), hypercalcemia,hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia ofmalignancy with or without bone metastases, rheumatoid arthritis,periodonritis, osteoarthritis, ostealgia, osteopenia, cancer cachexia,calculosis, lithiasis (especially, urolithiasis), solid carcinoma,mesangial proliferative glomerulonephritis, edema (e.g. cardiac edema,cerebral edema, etc.), hypertension such as malignant hypertension orthe like, premenstrual tension, urinary calculus, oliguria such as theone caused by acute or chronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No. 6,710,072 teaches the use of EP2 agonists for thetreatment or prevention of “osteoporosis, constipation, renal disorders,sexual dysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

These compounds can also be used to treat or prevent conditionsaffecting the posterior part of the eye including maculopathies/retinaldegeneration such as non-exudative age related macular degeneration(ARMD), exudative age related macular degeneration (ARMD), choroidalneovascularization, diabetic retinopathy, acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; uveitis/retinitis/choroiditis such asacute multifocal placoid pigment epitheliopathy, Behcet's disease,birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome;vasuclar diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, disseminated intravascularcoagulopathy, branch retinal vein occlusion, hypertensive funduschanges, ocular ischemic syndrome, retinal arterial microaneurysms,Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion,papillophlebitis, central retinal artery occlusion, branch retinalartery occlusion, carotid artery disease (CAD), frosted branch angiitis,sickle cell retinopathy and other hemoglobinopathies, angioid streaks,familial exudative vitreoretinopathy, and Eales disease;traumatic/surgical conditions such as sympathetic ophthalmia, uveiticretinal disease, retinal detachment, trauma, conditions caused by laser,conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (POHS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with accosiated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis.Preferably, the disease or condition is retinitis pigmentosa,proliferative vitreal retinopathy (PVR), age-related maculardegeneration (ARMD), diabetic retinopathy, diabetic macular edema,retinal detachment, retinal tear, uveitus, or cytomegalovirus retinitis.

These compounds are also useful in treating asthma.

Synthetic Methods

While there are many ways the compounds disclosed herein, one exemplarysynthesis may begin with commercially available N-Boc hydrazine (1, alsoknown as t-butyl carbazate, Aldrich Chemical Company, see Scheme 1).N-arylation occurs to give 2 according to Buchwald's copper-catalyzedprocedure (Org. Lett. 2001, 3, 3803-3805) using a wide variety ofsubstituted bromophenyl and other bromoaryl compounds a. The haloarenesa are either available commercially or may be made according topublished literature procedures. For example, U.S. patent applicationSer. No. 11/009,298, filed on Dec. 10, 2004 and U.S. Provisional PatentApplication 60/742,779 filed on Dec. 6, 2005, both of which areexpressly incorporated by reference herein, disclose methods of making anumber of useful substituted bromophenyl compounds. These procedures mayalso be readily adapted to other bromoaryl compounds such as substitutedbromothienyl, substituted bromofuryl, substituted bromopyridinyl,substituted bromonaphthyl, substituted bromobenzothienyl, and the like.Intermediate 2 is then alkylated on N′ using electrophiles b to provideintermediate 3.

Examples of b include ethyl 7-bromoheptanoate (commercially availablefrom Aldrich Chemical Company) and methyl 7-bromohept-5-ynoate (Org.Synth. 1993, Collect. Vol. VIII, 415-420). Examples of b also includeelectrophiles bearing aryl and heteroaryl groups (e.g. methyl4-(2-bromoethyl)benzoate [available in one step from commerciallyavailable 4-(2-bromoethyl)benzoic acid] and methyl5-(3-bromopropyl)-thiophene-2-carboxylate [see WO 94/13295, incorporatedby reference herein]). Other methods for preparing b are readilyascertained by those of ordinary skill in the art based upon thisdisclosure.

In another hypothetical example, benzophenone hydrazone (4, Aldrichchemical company) serves as the stating material (see Scheme 2). In thiscase, N′-arylation occurs to give 5 according to Buchwald'spalladium-catalyzed procedure (J. Am. Chem. Soc. 1998, 120, 6621-6622)using a wide variety of substituted bromophenyl and other bromoarylcompounds a. Deprotection reveals the aryl hydrazine 6 which isprotected to give N-Boc-N′-aryl hydrazine 7. A large variety ofsubstituted aryl hydrazines such as 6 are commercially available.

Intermediates 2 and 7 are regioisomers. In certain cases, the copperchemistry used to arrive at 2 will also afford compound 7 (see Buchwald,above, and Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729).Palladium-catalyzed arylation may also afford mixtures of regioisomers(Wang, et al., Tetrahedron Lett. 1999, 40, 3543-3546), mainly favoringisomer 2. This represents an alternative approach to compound 7.

Intermediate 3 may be acylated or sulfonylated using an appropriate acylor sulfonyl halide d to afford intermediate 8. Removal of the Bocprotecting group then affords compound 9 (Scheme 3). Compound 9 can beconverted to compound 20 by ester hydrolysis using either lithiumhydroxide/tetrahydrofuran/H₂O or rabbit liver esterase/pH 7.2buffer/methylcyantide. Compound 20 can be converted to compound 13 usingethyl chloroformate/triethylamine/dichloromethane followed by Y—OH.

In another hypothetical example, intermediate 7 may be acylated orsulfonylated using an appropriate acyl or sulfonyl halide d to affordintermediate 10. Removal of the Boc protecting group and alkylation ofthe resulting amine 11 then affords compound 12 (Scheme 4). Compound 12can be converted to compound 21 by ester hydrolysis using either lithiumhydroxide/tetrahydrofuran/H₂O or rabbit liver esterase/pH 7.2buffer/methylcyantide. Compound 21 can be converted to compound 22 usingethyl chloroformate/triethylamine/dichloromethane followed by Y—OH.

Compounds 9 and 12 may be the target compounds, or may requiredeprotection(s) and/or functionalization (depending on the nature of Band Y) to arrive at the target compounds.

Based upon this disclosure, numerous other ways of preparing thecompounds disclosed herein will be apparent to a person of ordinaryskill in the art.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

Treatment of inflammatory bowel disease may be accomplished by theadministration of the compounds described herein to the sufferingmammal. Inflammatory bowel disease describes a variety of diseasescharacterized by inflammation of the bowels including, but not limitedto, ulcerative colitis and Crohn's disease. Treatment may beaccomplished by oral administration, by suppository, or parenteraladministration, or some other suitable method.

While not intending to limit the scope of the invention in any way,delivery of the compounds disclosed herein to the colon via oral dosageforms may be accomplished by any of a number of methods known in theart. For example, reviews by Chourasia and Jain in J Pharm PharmaceutSci 6 (1): 33-66, 2003 and Shareef et. al (AAPS PharmSci 2003; 5 (2)Article 17) describe a number of useful methods. While not intending tolimit the scope of the invention in any way these methods include 1)administration of a prodrug, including an azo or a carbohydrate basedprodrug; 2) coating the drug with, or encapsulating or impregnating thedrug into a polymer designed for delivery to the colon, 3) time releaseddelivery of the drug, 4) use of a bioadhesive system; and the like.

While not intending to be bound in any way by theory, it is believedthat intestinal microflora are capable of reductive cleavage of an azobond leaving the two nitrogen atoms as amine functional groups. Whilenot intending to limit the scope of the invention in any way, the azoprodrug approach has been used to deliver to 5-aminosalicylic acid tothe colons of humans in clinical trials for the treatment ofinflammatory bowel disease. It is also believed that bacteria of thelower GI also have enzymes which can digest glycosides, glucuronides,cyclodextrins, dextrans, and other carbohydrates, and ester prodrugsformed from these carbohydrates have been shown to deliver the parentactive drugs selectively to the colon. For example, in vivo and in vitrostudies on rats and guinea pigs with prodrugs of dexamethasone,prednisolone, hydrocortisone, and fludrocortisone, suggest thatglycoside conjugates may be useful for the delivery of steroids to thehuman colon. Other in vivo studies have suggested that glucouronide,cyclodextrin, and dextran prodrugs of steroids or non-steroidalanti-inflammatory drugs are useful for delivery of these drugs to thelower GI tract. An amide of salicylic acid and glutamic acid has beenshown to be useful for the delivery of salicylic acid to the colon ofrabbit and dog.

While not intending to limit the scope of the invention in any way,carbohydrate polymers such as amylase, arabinogalactan, chitosan,chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, orazo-group containing polymers can be used to coat a drug compound, or adrug may be impregnated or encapsulated in the polymer. It is believedthat after oral administration, the polymers remain stable in the upperGI tract, but are digested by the microflora of the lower GI thusreleasing the drug for treatment.

Polymers which are sensitive to pH may also be used since the colon hasa higher pH than the upper GI tract. Such polymers are commerciallyavailable. For example, Rohm Pharmaceuticals, Darmstadt, Germany,commercially provides pH dependent methacrylate based polymers andcopolymers which have varying solubilities over different pH rangesbased upon the number of free carboxylate groups in the polymer underthe tradename Eudragit®. Several Eudragit® dosage forms are currentlyused to deliver salsalazine for the treatment of ulcerative colitis andCrohn's disease. Time release systems, bioadhesive systems, and otherdelivery systems have also been studied.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the claims.

1. A compound which is a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interphenylene or monocyclic heterointerarylene, the sumof m and o is 1, 2, 3, or 4, and wherein one CH₂ may be replaced by S orO; E is SO₂, CO, or CS; G is alkyl, aryl or heteroaryl having 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms; and B is substituted aryl orsubstituted heteroaryl.
 2. A compound according to claim 1 which is astructure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof; Ris hydrogen or C₁₋₁₀ hydrocarbyl.
 3. A compound according to claim 1which is a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof; Ris hydrogen or C₁₋₁₀ hydrocarbyl.
 4. A compound according to claim 1wherein A selected from the group consisting of (3-methylphenoxy)methyl,(4-but-2-ynyloxy)methyl, 2-(2-ethylthio)thiazol-4-yl,2-(3-propyl)thiazol-5-yl, 3-methoxymethyl)phenyl, 3-(3-propylphenyl,3-methylphenethyl, 4-(2-ethyl)phenyl, 4-phenethyl, 4-methoxybutyl,5-(methoxymethyl)furan-2-yl, 5-(methoxymethyl)thiophen-2-yl,5-(3-propyl)furan-2-yl, 5-(3-propyl)thiophen-2-yl, 6-hexyl, and(Z)-6-hex-4-enyl.
 5. A compound according to claim 1 wherein B selectedfrom the group consisting of 4-(1-hydroxy-2,2-dimethylpropyl)phenyl,4-(1-hydroxy-2-methylpropan-2-yl)phenyl,4-(1-hydroxy-2-methylpropyl)phenyl, 4-(1-hydroxybutyl)phenyl,4-(1-hydroxyheptyl)phenyl, 4-(1-hydroxyhexyl)phenyl,4-(1-hydroxypentyl)phenyl, 4-(1-hydroxypropyl)phenyl,4-(3-hydroxy-2-methylheptan-2-yl)phenyl,4-(3-hydroxy-2-methyloctan-2-yl)phenyl,1-hydroxy-2,3-dihydro-1H-inden-5-yl, 2,3-dihydro-1H-inden-5-yl,3-(hydroxy(1-propylcyclobutyl)methyl)phenyl,4-(1-hydroxy-5,5-dimethylhexyl)phenyl,4-(hydroxy(1-propylcyclobutyl)methyl)phenyl, 4-tert-butylphenyl,4-hexylphenyl, 4-(1-hydroxy-2-phenylethyl)phenyl,4-(1-hydroxy-3-phenylpropyl)phenyl, 4-(1-hydroxycyclobutyl)phenyl,4-(2-cyclohexyl-1-hydroxyethyl)phenyl,4-(3-cyclohexyl-1-hydroxypropyl)phenyl,4-(cyclohexyl(hydroxy)methyl)phenyl, 4-(cyclohexylmethyl)phenyl, and4-(hydroxy(phenyl)methyl)phenyl.
 6. A compound according to claim 1which is a structure


7. A compound according to claim 1 which is a structure


8. A compound according to claim 1 which is a structure


9. A compound according to claim 1 which is a structure


10. A compound according to claim 1 which is a structure


11. A compound according to claim 1 which is a structure


12. A compound according to claim 1 which is a structure


13. A compound according to claim 1 which is a structure


14. A method of treating glaucoma or ocular hypertension in a mammalusing the compound of claim
 1. 15. A compound for treatment of baldnesswhich is a formula selected from the group consisting of

Wherein Y is